Nanoparticles for drug delivery to the brain

The first successful delivery of a drug across the BBB occurred in 1995. The drug used was hexapeptide dalargin, an anti-nociceptive peptide that cannot cross the BBB alone. It was encapsulated in polysorbate 80 coated nanoparticles and intravenously injected. Most polymers used for nanoparticle drug delivery systems are natural, biocompatible, and biodegradable, which helps prevent contamination in the CNS. Several current methods for drug delivery to the brain include the use of liposomes, prodrugs, and carrier-mediated transporters. Many different delivery methods exist to transport these drugs into the body, such as peroral, intranasal, intravenous, and intracranial. For nanoparticles, most studies have shown increasing progression with intravenous delivery. Along with delivery and transport methods, there are several means of functionalizing, or activating, the nanoparticle carriers. These means include dissolving or absorbing a drug throughout the nanoparticle, encapsulating a drug inside the particle, or attaching a drug on the surface of the particle. == Types of nanoparticles for CNS drug delivery ==

Lipid-based One type of nanoparticle involves use of liposomes as drug molecule carriers. The diagram on the left shows a standard liposome. It has a phospholipid bilayer separating the interior from the exterior of the cell. Liposomes are composed of vesicular bilayers, lamellae, made of biocompatible and biodegradable lipids such as sphingomyelin, phosphatidylcholine, and glycerophospholipids. Cholesterol, a type of lipid, is also often incorporated in the lipid-nanoparticle formulation. Cholesterol can increase stability of a liposome and prevent leakage of a bilayer because its hydroxyl group can interact with the polar heads of the bilayer phospholipids. Liposomes have the potential to protect the drug from degradation, target sites for action, and reduce toxicity and adverse effects. This manufacturing process is already scaled and in use in the food industry, which therefore makes it more appealing for researchers and for the drug delivery industry. Liposomes can also be functionalized by attaching various ligands on the surface to enhance brain-targeted delivery. Cationic liposomes Another type of lipid-nanoparticle that can be used for drug delivery to the brain is a cationic liposome. These are lipid molecules that are positively charged. Nanoemulsions Another form for nanoparticle delivery systems is oil-in-water emulsions done on a nano-scale. and polycyanoacrylate (PCA). Some studies have found that polymeric nanoparticles may provide better results for drug delivery relative to lipid-based nanoparticles because they may increase the stability of the drugs or proteins being transported. Polymeric nanoparticles may also contain beneficial controlled release mechanisms. Nanoparticles made from natural polymers that are biodegradable have the abilities to target specific organs and tissues in the body, to carry DNA for gene therapy, and to deliver larger molecules such as proteins, peptides, and even genes. Further, the stealth effect, caused in part by the hydrophilic and flexible properties of the PEG chains, facilitates an increase in localizing the drug at target sites in tissues and organs. == Mechanisms for delivery ==

Liposomes A mechanism for liposome transport across the BBB is lipid-mediated free diffusion, a type of facilitated diffusion, or lipid-mediated endocytosis. There exist many lipoprotein receptors which bind lipoproteins to form complexes that in turn transport the liposome nano-delivery system across the BBB. Apolipoprotein E (apoE) is a protein that facilitates transport of lipids and cholesterol. MENs, proposed by the research group of Professor Sakhrat Khizroev at Florida International University (FIU), have been used for targeted drug delivery and externally controlled release across the BBB to treat HIV and brain tumors, as well as to wirelessly stimulate neurons deep in the brain for treatment of neurodegenerative diseases such as Parkinson's Disease and others. == Toxicity ==

A study was performed to assess the toxicity effects of doxorubicin-loaded polymeric nanoparticle systems. It was found that doses up to 400 mg/kg of PBCA nanoparticles alone did not cause any toxic effects on the organism. These low toxicity effects can most likely be attributed to the controlled release and modified biodistribution of the drug due to the traits of the nanoparticle delivery system. Toxicity is a highly important factor and limit of drug delivery studies, and a major area of interest in research on nanoparticle delivery to the brain. == Research ==

In the early 21st century, extensive research is occurring in the field of nanoparticle drug delivery systems to the brain. One of the common diseases being studied in neuroscience is Alzheimer's disease. Many studies have been done to show how nanoparticles can be used as a platform to deliver therapeutic drugs to these patients with the disease. A few Alzheimer's drugs that have been studied especially are rivastigmine, tacrine, quinoline, piperine, and curcumin. PBCA, chitosan, and PLGA nanoparticles were used as delivery systems for these drugs. Overall, the results from each drug injection with these nanoparticles showed remarkable improvements in the effects of the drug relative to non-nanoparticle delivery systems. This possibly suggests that nanoparticles could provide a promising solution to how these drugs could cross the BBB. One factor that still must be considered and accounted for is nanoparticle accumulation in the body. With long-term and frequent injections that are often required to treat chronic diseases such as Alzheimer's disease, polymeric nanoparticles could potentially build up in the body, causing undesirable effects. This area for concern would have to be further assessed to analyze these possible effects and to improve them. == References ==